Contents

Summary

Clinical Pharmacokinetics and Disease Proces es

Clinical Pharmacokinetics 15: 216-226 (1988) 0312-5963/88/00 I 0-0216/$05.50/0 © ADIS Press Limited All rights reserved.

Alfentanil Infusions in Patients Requiring Intensive Care

A. Bodenham and G.R. Park Department of Anaesthesia and Intensive Care, Addenbrooke's Hospital , Cambridge, England

Summary ........ ... ............. ........ .......... ......... .............. ........... ......... ... ..... ..... .... ........ ...... ... ........ .. ... 216 I. Clinical Pharmacology of Alfentanil ................................... .... ........... .... ................ ... .. ...... ... 217 2. Pharmacokinetics in Altered Pathophysiological States ................................ .... ....... .. .. ... ... 218

2.1. Age .................................... .. ........ .... .... ....... .. .... ..... ...... ...... .... ... ........ ... ............................ 218 2.2 Obesity ..... .... ..... ................... " ............... ... ...... ...... ........ ......... ..... ......... .. ............ .. .......... ... 219 2.3 Liver Disease .. ..................................... .. ....................... .... ........................... .. ...... ........ .. .. 219 2.4 Renal Insufficiency .... .... ................... ... .. ........... .... ....... ...... ......... ..... .......... ...... ............ ... 219 2.5 Hormonal Effects ................................ .... ......... .... ............. ... ...... ..... ....... ..... .... ...... .... ...... 220 2.6 Septic Shock ...... ......... ......... ..... ..... ........ .. ........ .... ........ .... ... ......... ...... .. .... ........ .... ... ... ...... 220 2.7 Plasma Protein Binding ..... .................. .. ......................................................................... 220 2.8 Influence of Pharmacogenetics ... .. ...................... ..... ................................ .. .................... 221 2.9 Population Pharmacokinetics .. ... .... ....... .. ..... ... ... ........................................................... 221

3. Drug Interactions with Alfentanil ....... ...... .. ........ .. .. ... ........ ..... .... ......................................... 221 4. Therapeutic Use of Alfentanil .............................................................................................. 222

4.1 Clinical Implications .. ... ................................................. ............ .. ... ....... ..... ...... .............. 223 5. Tolerance .... .. ... ... ........ .. ....... ..... .... ....... ... ....... ... ............ ...... ..... ...... ............ .... ....... ... .. ........... .. 224 6. Adverse Effects of Alfentanil .. ......... ...... ...... ...... .................................... ..... ......... .. ............... 224 7. Conclusions ...................... ................ ......... .... ........ ...... ... .......... .. ........ ... ........... .... ... ............. .. 225

A((entanil is a short acting opioid that has an established place in anaesthesia. Its predictable pharmacokinetics and pharmacodynamiCS. particularly its rapid termination of effect and haemodynamic stability. have led to its use by continuous intravenous in­fusion both during anaesthesia and more recently in critically ill patients. Fine control of a potent analgesic that has respiratory depressant and antitussive properties would be particularly advantageous in this group. offering patients an improvement in comfort with­out increasing the risk of oversedation.

Pharmacokinetic studies of a((entanit have demonstrated wide interindividual vari­ations. This may be due to a wide variety of factors including age. obesity. hepatic dys­function . changes in regional haemodynamics. sex. and alterations in plasma protein bind­ing abitity and concentration. The importance of pharmacogenetic differences and tolerance to a((entanit remains to be elucidated. Renal disease does not appear to significantly alter the pharmacokinetics of this agent. which may make it particularly useful in this situation. Since a(fentanit does not depress conscious level or produce anxiolysis. additional agents such as a benzodiazepine will be necessary to provide adequate sedation.

The difficulties in accurately predicting the response of an individual critically ill patient

Alfentanil in Intensive Care 217

necessitate careful and continuous dose titration of a/fentanil according to the clinical response.

A plethora of analgesics, hypnotics, sedatives, tranquillisers, anti psychotics and muscle relaxants has been used for patients requiring analgesia and sedation during intensive care. The range of drugs available suggests that the ideal treatment regimen does not yet exist. Adverse reactions to alphado­lone plus alphaxalone (althesin) [Lawler et al. 1983] and reports of cortisol suppression with etomidate (Lambert et al. 1983; Ledingham & Watts 1983; Watts & Ledingham 1984) led to their withdrawal for sedation in critically ill patients. Midazolam has shown both disordered pharmacokinetics and pharmacodynamics in intensive care patients (Bryne et al. 1984; Byatt et al. 1984; Shelly et al. 1987). Opiates have also been shown to be prob­lematic after prolonged use in critically ill patients (Osborne et al. 1986; Shelly et al. 1986; Szeto et al. 1977). These problems with the newer drugs, and a general dissatisfaction with some of the more tra­ditional agents (Gast et al. 1984), have necessitated a continued search for new agents in this field. The advantages of the administration of drugs by con­stant infusion have been reported (Merriman 1981).

The ultimate aim of sedation and analgesia in intensive care is patient comfort, i.e. the patient should be pain free, not anxious, and may be either awake or drowsy. Amnesia for unpleasant events and procedures may also be beneficial. Deep se­dation with an unrousable patient is now reserved for a few specific indications and is currently thought to be undesirable. Sedation is usually achieved by the use of drugs such as benzodiaze­pines, analgesia is usually achieved by the use of opiates. Some opiates do possess sedative effects, but while it would be ideal if 1 drug could satis­factorily produce both sedation and analgesia, the current therapeutic armamentarium does not in­clude such a drug. Table I provides a list of the properties that would be possessed by the ideal se­dative/analgesic drug. Alfentanil, a new short-act­ing narcotic that has been evaluated in this area,

Table I. Properties that would be possessed by the ideal

sedative/analgesic

Rapid onset of analgesic and sedative effect Rapid reversibility to allow assessment of cerebral function

No accumulation following prolonged administration Unchanged elimination in impaired hepatiC or renal function Lack of chronic toxicity, enzyme induction and tachyphylaxis Reliable pharmacodynamics affected as little as possible in shock; hypoproteinaemia; water, electrolyte or acid-base

imbalance Pharmacokinetic profile suitable for use by infUSion allowing

easy dose adjustment Predictable dose-dependent depression of respiration Cardiovascular stability No adverse endocrinological effects Minimum immunological or metabolic effects High therapeutic ratio Absence of active metabolites No psychic or physical withdrawal symptoms on discontinuation of treatment No interactions with other drugs

may possess many of the characteristics of this ideal drug.

The aim of this article is to review the available pharmacokinetic data for alfentanil, particularly as they relate to its use in intravenous infusions.

1. Clinical Pharmacology of Alfentanil

A comparison of the pharmacokinetic proper­ties of alfentanil with other opiate drugs is shown in table II. [For a more detailed account of the pharmacokinetics of alfentanil see Hug and Chaff­man (1984).] Of importance in the context of con­tinuous infusions are its small volume of distri­bution at steady-state (V dss), short elimination half­life (tlh~) and lack of active metabolites. Active me­tabolites have been found after metabolism of morphine (Osborne et al. 1986; Shelly et al. 1986), pethidine (meperidine) [Szeto et al. 1977] and re­lated compounds. Although fentanyl is not known

Alfentanil in Intensive Care

Table II. Mean pharmacokinetics of different opiates in adults

Drug Vd •• CL t'l2" Reference

(L/kg) (L/kg/h) (h)

Alfentanil 0.39 0.20 1.63 Bower & Hull

(1982)

Fentanyl 4.8 1.3 3.09

Morphine 3.2 0.90 2.9 Stanski et al.

(1978)

Pethidine 3.7 0.84 3.7 Mather et al.

(1975)

Abbreviations: Vds• = volume of distribution at steady-state;

CL = total body clearance; t'l2~ = elimination half-life.

to have the same problems with active metabolites as these agents, it remains to be properly investi­gated in critically ill patients. Additionally, after prolonged infusion it may change from having a redistribution limitation of effect to being clear­ance limited (Mather et al. 1983). These features currently limit its use in critically ill patients. These pharmacokinetic differences to alfentanil are re­flected in the short duration of intense analgesia after alfentanil administration that allows the rapid termination of clinical effects when the infusion is stopped.

The pharmacokinetics of alfentanil in intensive care patients have been investigated in 2 studies (Sinclair et al. 1988; Yate et al. 1986). The results from the latter are shown in table III. The elim­ination half-life of alfentanil was similar to that seen during intra-abdominal surgery, and clearance was similar to that seen during maintenance of anaes­thesia. This may reflect a fall in hepatic blood flow similar to that described during surgery (Gelman 1976).

In common with other opiates, alfentanil pro­duces respiratory depression which has been shown to be comparable to that produced by fentanyl (An­drews et al. 1983), although recovery is, predicta­bly, faster. The cardiovascular effects of alfentanil have been compared with those of fentanyl in an­aesthetised patients (Rucquoi & Camu 1983). Nei­ther drug induced profound cardiovascular depres­sion, but both improved myocardial oxygen

218

demand. These effects lasted for a shorter period with a bolus dose of alfentanil than with fentanyl.

Elimination of alfentanil occurs almost exclu­sively by metabolism, only 0.4% of a dose being excreted in the urine as unchanged drug (Schuttler & Stoeckel 1982). The main metabolic pathways are oxidative N- and O-dealkylation (Camu et al. 1982). No active metabolites have been found. The principal metabolite is noralfentanil although others have been identified (Lavrijsen et aI., unpublished observation).

The estimated hepatic extraction ratio of 0.3 to 0.6 {Bower & Hull 1982; Camu et aI. 1982; Ferrier 1985} suggests that the total body clearance of al­fentanil could be influenced by changes in both he­patic blood flow and intrinsic clearance (Reitz 1986). In contrast to fentanyl, the duration of effect of a single dose of alfentanil is relatively more de­pendent on total body clearance than on redistri­bution to tissues.

2. Pharmacokinetics in Altered Pathophysiological States

113 patients were investigated in the 5 studies evaluated for the purpose of this review. Only 2 studies involved a pharmacokinetic evaluation of alfentanil (Sinclair et aI. 1988; Yate et aI. 1986) and several potential problems in its use can be iden­tified from its varying pharmacokinetics during an­aesthesia (table IV).

2.1 Age

The pharmacokinetics of alfentanil have been studied in children undergoing anaesthesia (Meis­telman et aI. 1984, 1987; Strunnin et aI. 1986) in

Table III. Pharmacokinetics of alfentanil in patients (n = 14)

needing intensive care (Yate et al. 1986). For abbreviations, see

table II

Dose !P9/kg/min) Duration of infusion (h)

t'l2# (h) CL (L/h/kg)

Vd.s (L/kg)

0.46 ± 0.028

17.2± 0.56

2.7 ± 0.4

0.16 ± a.Ol 0.59 ± 0.09

Alfentanil in Intensive Care

Table IV. Pharmacokinetics of alfentanil in various patient groups. For abbreviations, see table II

Patient group CL VOss tv,,, Reference

(L/kg/h) (L/kg) (min)

Healthy 0.40 0.86 94 Bovill et al. subjects (1982) Elderly 0.26 0.54 137 Helmers et al.

(1984) Children 0.47 0.41 70 Strunnin et al.

(1986) Cirrhosis 0.10 0.40 219 Ferrier et al.

(1985) Uraemia 0.32 0.30 58 Van Peer et

al. (1986) Obesity 172 Bentley et al.

(1983)

whom they showed a significantly higher clearance, shorter elimination half-life and a smaller volume of distribution. Children may therefore need a higher rate of infusion for their body size than adults. In the elderly (over 65 years) the reverse has been shown, i.e. decreased clearance and pro­longed elimination half-life (Helmers et al. 1984). Further evaluation demonstrated that an equal dose of alfentanil had a greater effect on blood pressure in the elderly than in the young adult (Helmers et al. 1985), indicating the need for reduced dosage with increasing age. This has been supported by a pharmacodynamic study (Scott & Stanski 1985) which showed that with increasing age there was a significant decrease in the dose of alfentanil needed to induce 5-waves on the EEG.

It would appear, therefore, that the elderly re­quire less alfentanil than young adults, who, in tum, require less than children to achieve the same re­sult. The study by Cohen and Kelly (1987) has con­firmed the difference between the doses required by younger and older adults.

2.2 Obesity

A study by Bentley et al. (1983) in 6 obese adults demonstrated that obesity does not appear to affect the maximum plasma concentrations or volume of distribution, but does decrease clearance and pro-

219

long the elimination half-life of alfentanil (Bentley et al. 1983). However, Maitre et al. (1987) have shown no effect on clearance but a direct relation­ship with the volume of the central compartment. Although definite conclusions from these studies cannot be made, because of the small patient num­bers in obese patients, if the initial infusion rate is to be calculated on bodyweight, then this dose should be determined on lean body mass.

2.3 Liver Disease

Alfentanil is metabolised in the liver. Thus, when it is administered to patients with cirrhosis (Ferrier et al. 1985), elimination half-life is pro­longed. In addition, when the pharmacokinetic parameters were corrected for protein binding, the unbound volume of distribution and free-drug clearance were decreased significantly. Since the concentration of ai-acid glycoprotein, to which al­fentanil is mainly bound, was not different from a control group, it was suggested that the increase in the free fraction is caused by an alteration of bind­ing sites in cirrhotic patients possibly due to a plas­matic factor (Marshall & Williams 1987) or an al­teration in this protein. This may enhance the effects of alfentanil (Ferrier et al. 1985).

A bolus dose study performed on patients fol­lowing orthotopic liver transplantation also dem­onstrated similar changes (unpublished observa­tions).

In the presence of hepatic failure alfentanil must be used with caution, as it would appear that the effects of the drug may not only be prolonged, but also enhanced.

2.4 Renal Insufficiency

Alfentanil is primarily metabolised in the liver, with little unchanged drug appearing in the urine. Therefore, its effects should not be prolonged in renal failure, unlike those of morphine (Osborne et al. 1986; Shelly et al. 1986), pethidine (Szeto et al. 1977) and related compounds.

Van Peer et al. (1986) administered a bolus dose of alfentanil to 9 patients with chronic renal dys-

Alfentanil in Intensive Care

function and reported a significantly smaller vol­ume of distribution and a shorter elimination half­life. The reduced volume of distribution may be due to a reduction in the free fraction of alfentanil due to an increase in plasma ai-acid glycoprotein concentrations (Perucca et al. 1985). No significant relationship between alfentanil clearance and serum creatinine was demonstrated. All patients in this study resumed spontaneous breathing immediately after the end of the anaesthetic procedure.

In summary, alfentanil appears to be a suitable analgesic agent to use in patients with renal failure.

2.5 Hormonal Effects

A study of patients during anaesthesia and sur­gery has shown that the initial rise in stress hor­mones may be attenuated by alfentanil, although in the postoperative period hormone levels rose to match those in control groups (De Lange et al. 1983; Hynyen et al. 1985; Moller et al. 1985). The rise in hormone levels after surgery was faster follow­ing alfentanil than fentanyl analgesia (Hynyen et al. 1985).

Two of the trials in patients requiring intensive care studied the effect of alfentanil infusions on cortisol concentrations. Yate et al. (1986) com­pared alfentanil and pethidine infusions and showed no significant difference in plasma concentration of cortisol between the 2 groups, either in the pre­operative period or on the first postoperative day. A marked response to the stress of surgery was seen in both groups. However, mean cortisol concen­trations after 3 hours of infusions were signifi­cantly lower in the alfentanil patients than in those receiving pethidine.

Sear et al. (1987) studied plasma concentrations of cortisol over a longer period and demonstrated a wide range of values (103 to 5100 nmolfL). One patient had an unexplained abnormally low plasma cortisol concentration for which no obvious mech­anism was proposed. The patient recovered with­out steroid supplements and had no clinical fea­tures of steroid deficiency.

These studies suggest that alfentanil does not in­hibit adrenal steroidogenesis, and no patient in any

220

trial has shown clinical features suggestive of adre­nal insufficiency.

2.6 Septic Shock

Patients suffering from septic shock have been shown to eliminate both midazolam (Shelly et al. 1987) and morphine (MacNab et al. 1986) abnor­mally.

Alfentanil metabolism may be simIlarly pro­longed in septic shock, but further specific studies are needed.

2.7 Plasma Protein Binding

Alfentanil is bound to plasma proteins to a greater degree (85%) than fentanyl (43%). Further­more, the binding of alfentanil to plasma proteins is less affected by change in blood pH than fen­tanyl. In contrast to fentanyl, alfentanil is not bound to the red blood cells (Meuldermans et al. 1982). These differences may be responsible for the lower clearance seen with alfentanil. Binding to ai-acid glycoprotein accounts for the majority of alfentanil plasma protein binding (Meistelman et al. 1985; Reitz 1986).

Intraindividual variations in ai-acid glycopro­tein may be caused by cardiopulmonary bypass (Hug et al. 1983) and other physiological stresses. This may affect the plasma binding of both fen­tanyl and alfentanil, but such variations are more likely to be clinically significant for alfentanil. The proportion of alfentanil bound to plasma proteins is independent of changes in blood pH and of its concentration (within the therapeutic concentra­tion range). In patients with alcoholic cirrhosis, the unbound fraction of alfentanil in plasma is in­creased due to a qualitative change in the binding affinity of alfentanil to ai-acid glycoprotein (Fer­rier et al. 1985). Lower plasma concentrations of a I-acid glycoprotein have been reported in the fe­tus and the neonate (Meistelman et al. 1985).

The clinical effects of changes in ai-acid glyco­protein are variable and the resultant alteration in free drug fraction difficult to predict (Perucca et al. 1985). If clinical effects are to be seen it will be in

Alfentanil in Intensive Care

the neonate and other patients with low plasma concentrations of a)-acid glycoprotein.

2.8 Influence of Pharmacogenetics

It has been proposed (Henthorn et al. 1985; McDonnell et al. 1982b) that genetic polymorph­ism in alfentanil metabolism may account for some of the wide interindividual variability in plasma clearance rates. Recent work suggests that some subjects (3 to 10% in Caucasian populations) are poor oxidisers of certain drugs, for example, spar­teine, phenacetin and debrisoquine, because they possess an abnormal cytochrome P450 isoenzyme (Sloan et al. 1978). On the basis of this work, it is possible that a small percentage of the population (3 to 10%) are extremely slow metabolisers of al­fentanil (McDonnell et al. 1982a). More recent studies have failed to demonstrate this abnormal­ity both in vitro using human liver microsomes (Lavrijsen et aI., unpublished observation) and in 3 human volunteers. One of these volunteers was known to have an abnormal cytochrome P450 but despite this demonstrated normal alfentanil phar­macokinetics (Meuldermans et aI., unpublished observation).

If there are slow metabolisers of alfentanil, this may be one explanation of the prolonged narcosis seen in 1 patient in the trial described by Yate et al. (1986). Midazolam has also been shown to have slow metabolism in a similar proportion of the population (Dundee et al. 1986). In the study by Hopkinson and O'Dea (1987) some patients took many hours to awaken, although it is not clear whether this was due to midazolam or alfentanil. Therefore, patients who are slow oxidisers may both be slow to awake and remain narcotised for a con­siderable period if they receive both alfentanil and midazolam.

At present, these patients cannot be identified in advance. Clinical determination of slow metab­olism of alfentanil is difficult when patients are re­ceiving artificial ventilation, as the major side ef­fect of prolonged respiratory depression is not apparent. Therapeutic drug monitoring may help identify slow metabolisers who are already receiv­ing infusions; a rising alfentanil plasma concentra-

221

tion would indicate the need to stop or slow the infusion.

An alternative approach is to decrease the in­fusion rate each day and allow either spontaneous ventilation or a small amount of discomfort to re­turn to ensure that the drug is being satisfactorily eliminated.

2.9 Population Pharmacokinetics

Maitre and his colleagues (1987) studied the ef­fects of six variables (age, bodyweight, sex, dura­tion of anaesthesia, concomitant administration of etomidate and/or inhalational anaesthetics) on al­fentanil pharmacokinetics in 45 patients during surgery. The duration and type of anaesthesia had no significant effect on alfentanil pharmacokinet­ics. However, increasing age (over 40 years) led to a decrease in total body clearance, while increasing bodyweight resulted in an increase in the volume of the central compartment. A small sex difference was demonstrated with the volume of distribution being 15% larger in the female group. In a subse­quent study the same group (Maitre et al. 1988) demonstrated that this information can, with rea­sonable accuracy, predict the plasma concentra­tions following intravenous boluses or infusions of alfentanil in patients undergoing surgery. Although this work is of great importance to anaesthesia its application to critically ill patients requires cau­tion. The pharmacokinetics and pharmacodyn­amics in this group change rapidly as their con­dition improves or deteriorates (Shelly et al. 1987). More information is required before this type of analysis is applied to patients requiring intensive care.

3. Drug Interactions with Alfentanil

Cimetidine is commonly used to prevent stress ulceration in critically ill patients, and delays the metabolism of alfentanil (Levron, unpublished data). The significance of this drug interaction has not been assessed clinically. No information is available about the influence of ranitidine on the pharmacokinetics of alfentanil, but its lack of he-

Alfentanil in Intensive Care

patic enzyme inhibition (Henry et al. 1980) makes it unlikely to depress the metabolism of alfentanil in the same way as cimetidine.

Episodes of prolonged awakening attributable to midazolam (Bryne et al. 1984; Byatt et al. 1984) have led to the investigation of propofol as a se­dative. Initial reports on its ability to produce rap­idly reversible sedation are encouraging (Grounds et al. 1987). However, propofol has been associated with episodes of bradycardia (Thompson & Yate 1987) and ventricular tachycardia (Penfold & Park 1987). Alfentanil has been reported as producing bradycardias during anaesthesia (although no sim­ilar episodes have been reported in the intensive care studies to date), and the combination ofthese two potentially dysrhythmogenic drugs will neces­sitate careful cardiovascular monitoring. Alfentanil is a pethidine derivative and may interact with monoamine oxidase inhibitors.

4. Therapeutic Use 0/ Al/entanil

Five trials have been reported to date in which the aim was to improve the patient's comfort using alfentanil in combination with a benzodiazepine. Two of these trials studied the pharmacokinetics of alfentanil given by infusion (Sear et al. 1987; Yate et al. 1986).

Yate et al. (1984), in an open study, investigated 10 patients requiring artificial ventilation over­night after open cardiac surgery. Most patients re­ceived alfentanil alone at a mean infusion rate of 0.4 ~g/kg/min for an average duration of 796 (range 540 to 1120) minutes. No patient appeared to de­velop tolerance to the effects of alfentanil, although this was not specifically studied, and no evidence of respiratory depression was detected in the post­infusion period. Although analgesia and sedation were not measured, no patient indicated that he was in pain or suffering discomfort. On follow-up interview, the patients had no recall of the period of artificial ventilation, although this probably re­flects the use of other drugs, such as benzodiaze­pines, since alfentanil has no reported amnesic ef­fects.

Yate et al. (1986), in a prospective double-blind

222

study, compared alfentanil infusions 0.4 ~g/kg/min (n = 14) with pethidine 10 mg/h infusions (n = 15) in patients requiring overnight artificial ventilation after open heart surgery. Alfentanil plasma con­centrations were measured for the purpose of cal­culating pharmacokinetics. Additional sedation was provided by intravenous bolus doses of midazolam 2.5mg. Sedation was assessed hourly by the nursing staff on a four point scale:

I. Patient asleep or awake but needing no more analgesia.

2. Mildly restless but answers no when asked if more analgesia required.

3. Mildly restless answering yes to the above. 4. Restless, difficult to ventilate or in obvious

pain. Further assessments were made for 6 hours after

the infusion was discontinued. Comparable seda­tion was achieved in both groups. It was suggested that the significantly fewer changes of dose rate in the alfentanil group indicated that sedation was easier to achieve with alfentanil than with pethi­dine. The results for recovery at the termination of the infusion in both groups were similar and acceptable in terms of lack of sedation, respiratory rate and PaC02•

One patient had an unexplained respiratory ar­rest after discontinuation of the alfentanil infusion, thus requiring treatment with naloxone. Phar­macokinetic studies, at this time, showed a pro­longed elimination half-life of alfentanil. The patient was restudied at a later date and found to have an elimination half-life of alfentanil at the higher end of the normal range (Yate & SebeI1987).

In a study by O'Dea and Hopkinson (1987) 43 patients who required sedation and analgesia in a general ICU were reviewed retrospectively. Each received an infusion of alfentanil (20mg) and mid­azolam (40mg) mixed in a single 50ml syringe. The infusion rate of the mixture was adjusted by the nursing staff throughout the period of intermittent mandatory ventilation (see section 4.1) according to individual patient requirements. Attempts were made to maintain the infusion at the minimum rate necessary to keep the patient pain free and set­tled on the ventilator. The mean infusion rate of

Alfentanil in Intensive Care

alfentanil required per day ranged from 0.34 to 0.66 mg/h, and that of midazolam 0.68 to 1.3 mg/h. The maximum infusion rate required at any time by any patient was 8.34 mg/h; the duration of in­fusion was I to 18 days.

Sedation and analgesia were unsatisfactory for 6% of the time that patients received the mixture of the 2 drugs. The mean time for awakening after cessation of the infusion was 3.8 hours, the max­imum being 23 hours. Clinical efficacy, together with ease of use of the technique, has led to the routine use of alfentanil and midazolam by infu­sion for patients who require artificial ventilation in this ICU.

Cohen and Kelly (1987) prospectively studied 16 patients requiring sedation in a general inten­sive care unit. An initial bolus of 25 ~g/kg of al­fentanil was given over 60 seconds before the in­fusion was started, unless the patient was already sedated. An initial infusion rate of 0.67 ~g/kgfmin was used for the first 20 minutes. Thereafter the infusion rate was adjusted between 0.1 and 2.0 ~gf kgfmin to achieve satisfactory sedation. If this could not be achieved in this way additional bolus doses of 3 ~g/kg were administered. Diazepam ('Diaze­muls') 0.075 to 0.125 mgfkg supplementation was used extensively at first, as the nurses w:ere unused to seeing awake patients receiving artificial venti­lation. Later wakefulness was seen as a benefit and diazepam not administered as the patients were comfortable, and able to help with physiotherapy and communicate with staff and relatives. Seda­tion was scored each hour on the following five point scale:

O. Asleep, no response to tracheal suction. I. Rousable, coughs with tracheal suction. 2. Awakes spontaneously, coughs or triggers

ventilator. 3. Actively breathes against ventilator. 4. Unmanageable. More than 75% of the scores were less than 3

during the period of study. The infusion rate var­ied widely between and within patients from a minimum of 0.08 ~gfkgfmin to 2.5 ~gfkgfmin. When the infusion r~te was compared in patients aged over 50 years to those aged less than 50 there

223

appeared to be a difference, the younger age group requiring more (mean infusion rate 1 ~g/kgfmin) than the older patients (mean infusion rate 0.4 ~g/ kgfmin).

In another study by Sinclair et al. (1988), 14 patients requiring sedation were studied prospec­tively. The alfentanil infusion was started at 24 ~gf kgfh and adjusted according to clinical needs. Bolus doses of midazolam (2.5 to 5.0mg) were given intravenously to provide sedation, if needed. Com­pliance with artificial ventilation for up to 6 days was rated as good in 79% of patients. Most patients required additional doses of a benzodiazepine to maintain sleep or to prevent poor conditions of ar­tificial ventilation developing. Four patients re­quired muscle relaxants at some stage. There was no relationship between incremental doses of mid­azolam used and the alfentanil infusion rate.

After alfentanil infusion, recovery was stated to be 'rapid', despite total doses in excess of 50mg. Comparison of the rate of alfentanil administra­tion in the first and second 24-hour periods of treatment did not show any increase in dose re­quirement indicating tolerance. All patients were able to maintain adequate respiration within 3 hours of the cessation of the infusion, and nalox­one was never required. One patient maintained adequate spontaneous respiration for 51 hours while continuing to receive an alfentanil infusion. An­other patient had an unexplained fall in plasma cortisol concentrations while receiving the infu­sion, which spontaneously recovered when the in­fusion was discontinued.

These and other patients were included in a re­port of a symposium (Sear et al. 1987) which re­ported similar findings. However, in addition, the results of a study comparing plasma cortisols in the alfentanil group with a group receiving morphine infusions are reported. No significant difference between the groups could be demonstrated.

4.1 Clinical Implications

Alfentanil is a potent narcotic analgesic, and al­though it has some intrinsic sedative action, this is not a pronounced feature. The optimum thera-

Alfentanil in Intensive Care

peutic effect of sedation and analgesia was ob­tained when alfentanil was administered with a benzodiazepine. In those trials in which alfentanil was given with midazolam or diazepam, the an­algesia and sedation obtained were, for the vast majority of patients, rated as excellent. If the dose of the 2 components was kept low enough the patients were awake and co-operative and could at times be weaned from the respirator. In 2 trials (Cohen & Kelly 1987; Hopkinson & O'Dea 1987) patients were able to make some respiratory efforts during the alfentanil infusion. Most intensive care ventilators incorporate a synchronised intermittent mandatory ventilation (SIMV) mode which allows the patient to breathe spontaneously between man­datory breaths. When SIMV is used routinely, the incidence of 'fighting the ventilator' is minimised, the depth of sedation necessary reduced, and the need to use muscle relaxants avoided. In 3 of the trials SIMV was used successfully, demonstrating the ability of alfentanil to induce analgesia without inducing significant respiratory depression.

4.1.1 Daily Dosage The mean daily dosage must be individually ti­

trated for each patient. It will depend upon the ill­ness, the amount of pain present and the patient's response to that drug. The need for analgesia and sedation will vary throughout the day. In common with many drugs administered to critically ill patients, the dose needs frequent reassessment by the patients' attendants. It is difficult to derive pre­cise, objective and quantitative criteria on how to judge the efficacy of alfentanil infusions. Various scores are described in the studies presented in this review. Further reviews on sedation scoring can be found in the articles by Shelly et al. (1986) and Bion (1988). In the studies described patients re­ceived a bolus loading dose of alfentanil (1 to 6mg) at intubation or before the start of the infusion if no previous opiate had been administered or if its effects were wearing off. The infusion was then started immediately and adjusted according to need. In 1 trial (Cohen & Kelly 1987) there appeared to be 2 distinct groups, separated by age. Patients over 50 years required a mean infusion rate of 0.4 !lg/

224

kg/min (1.6 mg/h), while those less than 50 years required a mean infusion rate of I JLg/kg/min.

In most studies doses in the range of 0.02 to 2.2 JLg/kg/min or 0.08 to 8 mg/h were necessary. It is important to realise that overdosage of alfentanil will not be clinically recognisable since the drug will cause neither significant depression in con­scious level nor cardiovascular instability if the patient is receiving artificial ventilation. At least daily the infusion rate should be decreased to avoid this problem. If discomfort returns the rate should be increased.

5. Tolerance

This has been described during fentanyl (McQuay et al. 1981; Schafer et al. 1983) and mor­phine (Marshall et al. 1985) infusions. It has not been reported in studies to date using alfentanil (Cohen & Kelly 1987), although tolerance might be expected. To be able to demonstrate tolerance is difficult, relying either on sensitive time-consum­ing pharmacodynamic or pharmacokinetic meas­urements. To date, this information has been dif­ficult to obtain in critically ill patients.

6. Adverse Effects 0/ A lfentanil

In spite of the routine intensive and invasive haemodynamic and laboratory monitoring prac­tised in critically ill patients in each of these studies there was no evidence of significant cardiovascular or biochemical side effects that could be attributed to alfentanil in any of the 5 studies reviewed. Bradycardia, occasionally noted when alfentanil is used during surgery, was absent, even with the high infusion rates used in some patients. No effects on liver function were noted, despite the large total doses used. Except for 1 patient, arterial blood gas analysis after cessation of the infusion showed no evidence of any residual respiratory depression or renarcotisation leading to deterioration of respi­ratory function (Yate & Sebel 1987).

Apart from I patient, there was no evidence of any adverse effects of alfentanil on the adrenal gland, as determined by plasma concentrations of cortisol (see above). No patient showed abnor-

Alfentanil in Intensive Care

mali ties of renal or hepatic function, nor of blood haematology, coagulation or fibrinolysis, that were thought to be attributable to alfentanil (Sinclair et al. 1988). No unexpected deaths attributable to al­fentanil occurred but many patients died as a result of the underlying pathology. Three patients vom­ited in the immediate postinfusion period. No signs of psychological or physical withdrawal symptoms were recorded in any patients.

7. Conclusions

Alfentanil infusions used carefully and appro­priately provide effective analgesia for patients re­ceiving intensive care. If sedation is required in ad­dition to analgesia, the concomitant use of a benzodiazepine would appear to be essential. With such a regimen, satisfactory patient comfort should be easily achieved.

The current knowledge on alfentanil infusions, the known unwanted effects of metabolites of other opioids (morphine, pethidine) and the lack of knowledge and alteration of pharmacokinetics after prolonged infusions of fentanyl suggest that alfen­tanil may be the opioid of choice in renal failure. In patients who have an unstable cardiovascular system it offers improved haemodynamic stability compared with other opiates (Kenny, personal communication).

Only 1 study compared alfentanil infusions with another opiate, pethidine, and concluded that it was a satisfactory alternative. Other studies have all been unanimous in documenting the ease of use of alfentanil; however, comparative studies are nec­essary to conclusively prove the advantages of al­fentanil.

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Authors' address: Dr G.R. Park, Department of Anaesthesia, Ad­denbrooke's Hospital, Cambridge CB2 2QQ (England).